Recent advances in the multicomponent synthesis of heterocycles using tetronic acid

Tetronic acid, a versatile synthon, has been extensively investigated by numerous researchers in synthetic chemistry due to its crucial role in synthesizing heterocycles which makes this compound particularly advantageous in both pharmaceutical and biological fields. Various heterocycles can be synthesized using it as a precursor via multicomponent reactions (MCRs). Dicarbonyl groups can be considered the building blocks and key structural motifs of a wide range of natural compounds, which may contain different functional groups in the synthesis of heterocyclic frameworks. This review covers the literature from 2017 to 2022, and it encompasses the different one-pot protocols for synthesizing a variety of heterocyclic molecules.


Introduction
Given the paramount signicance of human health and hygiene, researchers in medicinal chemistry continue to pursue the synthesis of bioactive molecules with unrelenting vigor. These efforts aim to develop effective treatments for various diseases and to restrain the transmission of infectious diseases. 1,2 The design and preparation of cost-effective drugs that establish high efficacy with minimal side effects is a vital objective for researchers in this eld, to combat a variety of diseases. To achieve this goal, considerable effort has been dedicated to the synthesis and screening of candidate molecules to ensure low toxicity and side effects. 3,4 Furthermore, novel drug discovery has been transformed by this emerging paradigm. The main backbone and structure of most organic compounds made so far are composed of heterocycles. 5 This emerging paradigm has substantially revolutionized the eld of novel drug discovery. Notably, heterocycles are the primary backbone and structure of numerous synthesized organic compounds. In the context of versatile heterocyclic motifs, tetronic acids (4-hydroxy-[5H]furan-2-one) have been Ramin Javahershenas was born in Urmia, Iran, in 1971. He received his B.Sc degree in Applied Chemistry from Tabriz University, Tabriz, Iran, in 1993, his M.Sc. degree in Organic Chemistry from Urmia University, Urmia, Iran, under the supervision of professor Naser Ardabilchi in 1999, and his PhD degree in Organic Chemistry from Urmia University, Urmia, Iran under the supervision of professor Jabbar Khalafy, in 2017. His research interests include organic synthesis, heterocyclic synthesis, asymmetric synthesis, natural products synthesis, synthetic methodology, and applications of various catalysts in multicomponent reactions.
Sahand Nikzat was born in Tabriz, Iran, in 1995. He received his B.Sc in Applied Chemistry from Tabriz University, Tabriz, Iran, in 2018. Aer achieving a bronze medal in the National Olympiad exam in chemistry, he completed his M.Sc. degree in physical chemistry at the Sharif University of Technology, Iran, in 2021. His research focused on quantum-classical dynamics, which has broad applications in both organic and inorganic chemistry. In 2022, he joined the University of Toronto, Canada, to pursue his PhD in the eld of chemical physics. As a researcher with a profound interest in gaining in-depth knowledge across all elds of chemistry, he consistently conducts research in various areas to contribute to advancements in the scientic community.
proven to be a versatile and convenient building block. 6,7 This unique structural framework serves a pivotal role in organic synthesis owing to its relative presence in natural products. Consequently, their chemical and medicinal properties gained substantial interest. The overall structure and reactivity of tetronic acids along with nucleophilic and electrophilic active centers are shown in Fig. 1. 8,9 The biological and pharmaceutical activities of these compounds can distinguish them as noteworthy classes of chemical substances. For instance, nitrogen and oxygen based heterocyclic frameworks can be regarded as a distinguished category due to their extensive abundance in natural compounds. 10 Recently, the focus of pharmaceutical chemists has progressively shied towards tetronic acids and their derivatives, prompted by the diverse therapeutic properties these compounds demonstrate, and this interest has catalyzed the development of innovative methodologies.
Within the class of natural ve-membered heterocycles featuring O-substituted derivatives, tetronic acids (4-hydroxy- [5H]furan-2-ones) stand out owing to their profusion. A substantial number of natural compounds that stand for this particular heterocyclic structure have been identied, as illustrated in Fig. 2. The most notable instances of these compounds are penicillin and ascorbic acid (vitamin C). 11,12 There is noteworthy attention on tetronic acid derivatives as a result of their diverse biological and metabolic activities. These include functioning as anti-inammatory, 13 anticancer, 14 anti-HIV-1 protease, 15 antiepileptic, 16 antibiotic, 17,18 antifungal, 19 anticoagulant, 20 antibacterial, 21 analgesic, 22 and insecticidal agents. 23 A multicomponent reaction involves assembling products from multiple starting materials in a single-step protocol (MCRs). The utility of MCRs in facilitating the synthesis of diverse chemical structures has been recognized for over a century. Drug companies may take advantage of multicomponent reactions (MCRs). These reactions can be utilized to synthesize highly functionalized, biologically relevant natural and active molecules, including polycyclic structures.
Moreover, MCRs can be employed to boost various processes within pharmaceutical synthesis. Organic chemists primarily employ multicomponent reactions in the design and preparation of intricate, polycyclic molecules. The appeal of these reactions lies in their ability to minimize by-product formation, optimize energy consumption, reduce reaction times, maximize yields, and enhance selectivity. As such, the amalgamation of one-pot multicomponent strategies with diverse methodologies expedites the synthesis of biologically pertinent heterocycles, a cornerstone of 21st-century organic chemistry. [24][25][26][27][28] In a bid to extend research in the eld of heterocyclic scaffold synthesis through multicomponent reactions, [29][30][31][32][33][34] this work emphasizes the recurrent use of tetronic acid as an initial substrate in the synthesis of these compounds. The objective of this study is to examine the recent advancements in multicomponent reactions involving tetronic acid, a highly versatile moiety in heterocyclic chemistry, as a central structural motif for heterocyclic compounds. This review encompasses literature reports from the period 2017-2022.
Synthetic molecules can be categorized into four types according to their structural characteristics, which assist in their study. These types are organized based on the structural framework of the nal product, including N-heterocycle compounds, O-heterocycle compounds, spiro compounds, and miscellaneous compounds. This classication method provides an easier and more convenient approach to examining these molecules.   derivatives form an uncatalyzed reaction that occurs under mild conditions, thus offering the advantage of mild reaction conditions.

-d]pyrimidine
Pomerantz et al., described a novel synthesis of pyrido [2,3-d] pyrimidin (6), utilizing simple and readily available raw materials to generate a series of pyrido [2,3-d]pyrimidin (6) in yields ranging from low to high (Scheme 2). The synthesis of dihydropyridine was achieved through a three-component condensation of tetronic acid (1), various substituents of benzaldehyde (2), and uracil (5) as starting materials, yielding the corresponding desired products. The methodology to prepare various pyrido [2,3-d]pyrimidine proposes numerous advantages, such as brief reaction times, methodological simplicity, and comfortable reaction conditions. Moreover, the application of a straightforward washing method sufficed for the isolation of pure compounds, circumventing the necessity for rigorous chromatographic techniques. 36
A comprehensive study has investigated a broad spectrum of synthetic compounds for their anticancer and antitumor properties. The types of cancers tested in this study encompassed cells from breast, colon, lung, gastric, prostate, and cervical cancers.

Furo[3,4-b]pyrazoloquinoline
The Rong group developed a new approach that combines in situ reduction and annulation to synthesize pyrazolo[3,4-f] quinoline (12) and pyrazolo[4,3-f]quinoline derivatives (15). These were obtained by the cycloaddition of 5-nitroindazoles (13) in a 1,3-dipolar form, and 6-nitroindazoles (14) using different aromatic aldehydes (2), along with tetronic acid (1) in the presence of SnCl 2 $2H 2 O (Scheme 4). This method outperforms traditional synthetic methods due to several advantages, including stable reagents, simplicity, easy access to inexpensive raw materials, and high yields. In this highly efficient in situ reduction method, SnCl 2 $2H 2 O is used to simultaneously reduce nitro compounds and form a ring. Furthermore, this process provides a suitable alternative strategy for synthesizing scaffolds for other applications. The structural reliability of the synthetic compound 11-(4nitrophenyl)-8,11-dihydrofuro[3 ′ ,4 ′ :5,6]pyrido[3,2-f]quinoxalin-10(7H)-one was conrmed via X-ray diffraction analysis. This simple and practical method paves the way for the synthesis of fused tetracyclic heterocycles without the need for heavy catalysts. Utilizing fractions of tetracyclic amines, pyridine, and furan, this method offers the advantages of operational simplicity and avoids the necessity for separate intermediates in the reaction. 39

Dihydrofuro[3,4-b]quinoline
Laurentiz et al., have developed a straightforward and efficient method for synthesizing dihydroquinoline lactone derivatives (19). This process, which yields good to high results, involves the reaction of tetronic acids (1), aryl anilines (18), and aromatic aldehydes (2) in reuxing ethanol (Scheme 6). 40 In subsequent studies, synthetic compounds were tested for antibacterial activity under laboratory conditions against various bacterial strains, including Streptococcus mitis, Prevotella nigrescens, Streptococcus sanguinis, and Porphyromonas gingivalis. In addition, these compounds were screened for their effectiveness against Mycobacterium avium, Mycobacterium tuberculosis, and Mycobacterium kansas. An analysis of the results revealed that these compounds were particularly effective against Gram-negative bacteria. The inuence of side groups on the activity of these compounds was also assessed. Findings indicated that the presence of a methylenedioxy group on the dihydroquinoline ring and a nitro group on the structure-activity ring enhanced the antibacterial activity of the derivatives.
The mechanism of the reaction was demonstrated through the interaction between anilolactone (29), benzaldehyde (2), and malononitrile (20) This was further transformed into its enamine form. The desired product (30) was nally obtained through cyclocondensation and tautomerization, facilitated by the intramolecular nucleophilic attack of the enamine N atom on the cyano group. This reaction, upon the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), resulted in the generation of naphtho[2,3-f]quinoline lactone compounds (32) with yields ranging from satisfactory to high. 42 The UV-vis and uorescence spectra, as well as the optical absorption and emission properties of these synthetic derivatives, were studied in various solvents and at different pH levels. Emission bands in the range of 453-517 nm were observed for these derivatives, along with a bathochromic shi (597 nm) attributed to excited-state intramolecular proton transfer (ESIPT) in the case of a compound (R 1 = 3,4-(OH) 2 ). This compound showcased this catalysis. Although its luminescence properties were still preliminary, the results indicated its potential use as a chemical sensor across different solvents and pH levels.
compounds displayed highly potent inhibitory activities with IC50s > 40 nM against SK-Lu-1 and HepG2 cell lines, and for non-cancerous Hek293 cell lines had less toxicity.
Novel bioactive naphthoquinone-fused podophyllotoxins with uoroand triuoromethyl scaffolds have been synthesized by Van Kiem et al., and produced satisfactory yields with the use of MW by the one-pot multicomponent condensation of 2-amino-1,4-naphthoquinone (32), tetronic acid (1), and uorinated aryl aldehydes (2) in glacial acetic acid at 120°C (Scheme 12). Additionally, some of the products studied were examined for their anticancer activity, and the results showed that some had promising anticancer properties against human embryonic kidney cells (Hek-293) 44 A new class of agents with potential antitumor activity, known as podophyllotoxin-naphthoquinone derivatives (33), are derived from 2-aminonaphthalene-1,4-dione (32) in Scheme 13 in the same procedures as described. 45 In a separate study, Van Nguyen et al., showed that microwave-assisted three-component reactions can be used to synthesize podophyllotoxin-naphthoquinone compounds (33) using the stepwise thermal reaction. 46 The cytotoxicity prole of each synthetic compound was tested against four cancerous cell lines (MCF7, A549, KB, and HepG2) as well as against a noncancerous cell line, Hek-293. In particular, it was found that treatment of SK-LU-1 cells with compounds (Ar = 3-OMeC 6 H 5 and 3-BrC 6 H 5 ) resulted in an arrest of the G2/M phase of the cell cycle, activation of caspase-3/7, and an increase in apoptosis. Moreover, the results of a molecular binding study of these compounds showed that they had an outstanding interaction with the residues in the tubulin colchicine binding site.

Tetrahydro-1H-benzo[b]furo[3,4-e][1,4]diazepine
Naeimi et al., presented a clean, efficient, and straightforward procedure for the ultrasound-assisted multicomponent synthesis of biologically relevant benzodiazepine molecules (26) with tetracyclic frameworks. The process involves reactions between tetronic acid (1), aldehydes (2), and o-phenyldiamine  approach enables the rapid production of benzodiazepine structures using ultrasound, offering the advantages of speed, cleanliness, and experimental convenience. The catalyst, which can be easily applied using an external magnet, demonstrated consistent activity, suggesting potential for repeated use without signicant degradation in performance. 47

4H-Furo[3,4-b]pyran
A novel series of polyfunctionalized, biologically signicant 4Hfuro [3,4-b]pyran scaffolds (21) was synthesized by Singh et al., (Scheme 16). This was achieved via a facile, glycine-catalyzed, onepot multicomponent reaction. The process efficiently combined substituted benzaldehyde (2), malononitrile (20), and tetronic acid (1) in water at 60°C to yield the desired bioactive furo [3,4-b] pyran derivatives. This method is characterized by its benign environmental reaction conditions, high atomic economy, operational simplicity, cost-effectiveness, environmental compatibility, non-corrosiveness, and excellent performance. Moreover, it utilizes glycine as a cheap, readily available, and recoverable organocatalyst, eliminating the need for expensive metal catalysts. 48 Scheme 17 illustrates the proposed mechanism for synthesizing the desired heterocycles. Glycine effectively facilitates the Knoevenagel condensation of malononitrile (20) with an aldehyde (2). Subsequently, a Michael-type addition of tetronic acid (1) to the resulting cyanoolen intermediate (B) occurs. The electron pair on the oxygen atom then initiates an attack, leading to the formation of the proposed furopyran compound (21).

Benzoazulen-1-ones
Kamal et al., demonstrated a simple, one-pot method of synthesizing spirobenzodiazepines (37) that is environmentally friendly as well. In the presence of mild and cheap catalysts such as sulfamic acid in reuxing water, tetronic acid (1), o-phenylenediamine (22), and isatins (36) can be synthesized in excellent yields through three-component reactions in water (Scheme 22). In this synthesis, there is no need for organic solvents that are harmful to the environment. Instead, water is used as the reaction medium, which can be separated by ltering, washing, and drying without further purication. Some cytotoxic properties of all the synthesized compounds have also been studied about their ability to kill different human cancer cell lines. Based on the results of the studies, it was determined that a majority of the compounds show cytotoxic activity ranging from moderate to effective. 52 According to Scheme 23, the synthesis of spirobenzodiazepines is proposed to proceed through the formation of two C-N bonds and one C-C bond, consistent with the suggested mechanism. Initially, intermediate A is generated as a result of the reaction between o-phenylenediamine (25) and tetronic acid (1). Subsequently, the enamine attacks the keto group of isatin (41), assisted by one amino group of o-phenylenediamine. This is followed by a second attack by another amino group from the enamine, resulting in a cyclization with isatin (41)

Spiro polyfunctionalized fused
One of the useful and practical tools in organic and pharmaceutical synthesis is the combination of one-pot protocols and multiple bond-forming cascade transformations. Using these atom-economic processes with simple precursors could provide rapid access to natural complex product-like molecules. An efficient transition-metal-catalyzed cascade reaction was described by Haak et al., (Scheme 24) for the synthesis of biologically signicant spiro highly functionalized fused polycycle cycloadducts (41), (42), (43) from the reaction between 1-alkenyl propargyl alcohols (3-ethynyl-1,5-di-phenylpenta-1,4-dien-3-ol) (38) with tetronic acid (1) and 1,4-naphthoquinone (29) or dimethyl acetylenedicarboxylate (DMAD) (40) respectively using bifunctional (cyclopentadienone) and ruthenium complexes of type A (39) as a catalyst in triuoroacetic acid (TFA) in toluene at 100°C with high diastereoselectivity yields. Therefore, it is possible to achieve a common process with high selectivity for multiple fused cycles of various structures and functionalized bicyclic structures. Meanwhile, the cytotoxic activity of some novel pseudo-pharmaceutical structures was observed against KB cells. 53
According to Scheme 28,compounds (49) can be synthesized in the following way. A condensation of 2-hydroxynaphthalene-1,4-dione (28) with an aryl aldehyde (2) produces the intermediate A by Knoevenagel, which provides the conditions for the formation of arylidene ketone B aer losing the water molecule from the intermediate. As a result of Michael's addition of tetronic acid (1) to intermediate B, this intermediate is deprotonated, and in the nal step, it undergoes a 1,3-hydrogen shi to lead to the desired product (49).

Conclusions
Heterocycles, especially compounds with nitrogen or oxygen nuclei as their central structure, are of great interest in the development of compounds with biological and medicinal properties. Among compounds with dicarbonyl, tetronic acid derivatives can be used as an excellent starting material and a building block, and a key structural motif of natural compounds with different functional groups in the synthesis of heterocyclic frameworks. As a versatile synthon and a nucleus for the synthesis of complex heterocycles, MCRs of tetronic acid derivatives have recently made signicant progress. MCR strategies have also consistently been proven to be a powerful method for synthesizing diverse and complex molecular systems. Research on tetronic acid's uses in multicomponent reactions has been summarized in this review. This helped us synthesize a variety of polyfunctional heterocyclic scaffolds between 2017 and 2022.

Conflicts of interest
There are no conicts to declare.